The overall aim of this R01 resubmission is to develop vaccines against human schistosomiasis japonica. Schistosomiasis, caused by three principle species of dioecious trematodes (flatworms), currently infects over 250 million people world-wide and results in 1.53 million DALYs lost per annum. A recent reassessment of the global burden of schistosomiasis suggests that the actual health burden is 4 to 30 times greater than the previous WHO estimate. These tremendous figures underscore the impact a schistosomiasis vaccine would have on global human health. Although schistosomiasis is effectively treated with Praziquantel (PZQ), rapid reinfection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. We propose to capitalize on plasma samples and parasitologic data already collected during our previous R-01 funded studies, to identify novel antigens associated with resistance in humans. We will use a whole proteome, differential screening method to identify parasite antigens that are recognized by antibodies in plasma of resistant but not susceptible individuals. We will validate these candidates using high throughput immune profiling of antibody responses and analysis of these responses in the context of resistance to reinfection. We will extend the validation of these candidates by assessment of cellular immune responses in a newly enrolled cohort of S. japonicum infected individuals living in an endemic area of Leyte, the Philippines. Finally, candidates will be down-selected by bioinformatics, tissue- and stage- specific immunolocalization studies, and skin testing for hypersensitivity in S. japonicum infected buffalo. Four of these down-selected candidates will be evaluated for efficacy and safety (including hypersensitivity) in buffalo vaccine trials in Yrs 4 and 5. The outcome of these studies will be a list of validated antigens associated with resistance to reinfection in humans. These data will provide a strong basis to prioritize antigenic targets for additional preclinical safety and efficacy studies in both rodents and large animal models. These data will further the rational development of vaccines that limit reinfection and consequent morbidity and mortality in humans.